Capsule with fast content solubilization and release

ABSTRACT

The present invention relates to a capsule comprising a core and at least one envelope comprising at least one film-forming polymer, characterized in that it exhibits a total solubilization time for its envelope of less than or equal to 85 s, according to a test A, preferably less than or equal to 80 s, more preferably less than or equal to 70 s. 
     The invention also relates to the method of producing said capsule, and also to the products comprising said capsule, such as the food, pharmaceutical, oral hygiene or cosmetic products.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a U.S. national application of internationalapplication serial No. PCT/FR02/04034 filed Nov. 25, 2002, which claimspriority to French Patent Application No. 01/15277 filed Nov. 26, 2001.

TECHNICAL FIELD

The present invention relates to a capsule for rapid solubilization andrelease of the content.

BACKGROUND

In the fields in particular of food products and of oral care, theintention is to administer to an individual a compound such as an activeprinciple or an aromatic product. Various methods of administration havebeen developed, depending on the applications: powders, granules,capsules, microcapsules, liposomes, microspheres, etc. These variousmeans generally all exhibit characteristics relating to the protectionand/or to the release of the compound administered, suitable for thefinished product. They may in particular be physical (mechanical,temperature, etc.), chemical, (pH, water, ionic strength, etc.) orenzyme resistance, or properties of insolubility or of gradualsolubility (compounds which must be swallowed, gastro-resistantcompounds, etc.).

Interest will be focused more particularly here on capsules ormicrocapsules. Schematically, a capsule or microcapsule comprises a corecontaining the compound(s) to be vehicled [the content], and one or moreenvelopes, often based on gelatin. The difference between a capsule anda microcapsule is the size, which is more or less larger. In the presentpatent application, the term “capsule” will be used to denote capsulesand microcapsules.

The capsules known in the prior art can exhibit certain problems ofstability and leaktightness of the envelope, with in particularmigration of core constituents to the outside or migration of envelopeconstituents to the inside. Other problems encountered relate to theincorporation of one or more of the components into the core or theenvelope of the capsule, or further the method of production.

The capsules encountered are generally swallowed so as to release anactive agent in the stomach for example, or, on the contrary, must bekept in the mouth for a certain amount of time in order to allow theactive agent or the flavour to be released.

Mention is made herein of U.S. Pat. No. 5,300,305, which describes amicrocapsule for oral hygiene comprising a core surrounded by anenvelope which contains the active ingredients difficult to solubilizein the core. U.S. Pat. No. 5,370,864 describes a capsule for oralhygiene comprising a particular component in the core. U.S. Pat. No.5,286,496 describes a microcapsule for oral hygiene in which the coreand the envelope comprise active agents.

Certain patents refer to a capsule with several layers. Document EP 1020 177 describes a soft capsule comprising a first capsule in a secondcapsule, the second capsule dissolving in the stomach. U.S. Pat. No.6,200,603 describes a capsule comprising a core and an envelope providedwith an additional coating, which stabilizes the capsule and preventsmigration of certain compounds between the layers.

The problem of the rate at which a capsule breaks up has been studied.Specifically, for some applications, it is preferable for the capsule tobreak up rapidly, in order for the compound(s) transported to be rapidlyavailable.

Mention is in particular made herein of U.S. Pat. No. 5,620,707, whichdescribes small hard capsules suitable for flavoring a beverage,presented as dissolving rapidly in the beverage. Capsules producedaccording to this patent are mentioned hereinafter, by way of acomparative example.

However, in addition to the rate of breaking up, the solubilization ofthe capsule and more particularly of the envelope of the capsule shouldbe taken into account. The question raised is therefore what becomes ofthe envelope once it has broken up and released its contents. In fact,in many cases, the capsule envelope is slowly or incompletelyinsolubilized due to the internal or external crosslinking of thegelatin which it comprises. This effect prevents or slows down the rapidrelease of the content of the capsule and may, in addition, cause anunpleasant feeling in the mouth due to the nonsolubilized enveloperesidues, which will be referred to here as the “skin effect”.

Now, it is important, for certain applications, to be free of this skineffect, which causes an unpleasant feeling in the mouth.

U.S. Pat. No. 6,238,690 mentions this problem. In the description of theprior art of this patent, it is specified that capsules areconventionally formed using, for the envelope, film-forming materials ofthe gelatin type which have the drawback, besides the need to use acomplex method of production, of dissolving slowly while leaving anunpleasant residue in the mouth. In this patent, the solution providedis to use, as envelope material, not a film-forming material, but acarbohydrate in the glass state.

However, the problem remains for capsules in which the envelopecomprises a film-forming material.

SUMMARY OF THE INVENTION

After a great deal of research, the applicant has designed and developeda new capsule in which the envelope comprises a film-forming polymer,for rapid solubilization and release of the content. The capsuleaccording to the invention is solubilized very rapidly and, in addition,exhibits no skin effect; the solubilization of the envelope is thereforeoptimal. The invention thus concerns a capsule comprising a core and atleast one envelope comprising at least one film-forming polymer,characterized in that it exhibits a total solubilization time of itsenvelope of less than or equal to 85 s, according to a test A which isdefined below.

In this test A, a dissolving device having a continuous flow cell asdescribed in the French or American Pharmacopoeia (USP XXIII, 724) isused. This device makes it possible to model the solubility of thecapsule in the oral cavity. Use is preferentially made of a continuousflow cell rather than a conventional dissolving device for a capsule,due to the fact that the content of the capsule may be completelylipophilic and therefore sometimes float at the surface and not alwaysmake it possible to obtain homogeneous samples over time.

The procedure used in the test A is as follows: a single capsule isintroduced into the cell of a dissolving device as mentioned in theprevious paragraph, which cell is crossed by an aqueous flow maintainedat 37±0.5° C., pH 6.5, 50 ml/min. The capsule is then observed throughthe cell with the naked eye or using a camera combined with imageanalysis software (Microvision), making it possible to define a piercingtime (opening of the envelope), a breaking up time (total release of itscontent) and a total solubilization time (disappearance of the envelopeof the capsule). In the present patent application, the term“solubilization” is intended to mean the solubilization of the envelopeof the capsule, also called disintegration within the meaning of thePharmacopoeia.

The total solubilization time for the envelope of a capsule according tothe invention is less than or equal to 85 s according to the test A,preferably less than or equal to 80 s, more preferably less than orequal to 70 s. The breaking up time of a capsule according to theinvention is less than or equal to 30 s, preferably less than or equalto 20 seconds, more preferably less than or equal to 15 s.

Such a capsule, when it is ingested, therefore generates an immediateperception in the mouth of the active compounds which it contains.

A capsule according to the invention can be used as it is, as a finishedproduct or a new pharmaceutical form, or else as an ingredient ofanother pharmaceutical form or of another product. It can be solubilizedafter ingestion by the user, or solubilized in a medium which will beingested by the user.

A capsule according to the invention is not a soft capsule within themeaning of the state of the art; it is a capsule which feels hard, andwhich can break when it is pressed too hard between the fingers. Itshardness is of the order of 1 to 5 kg/cm².

DETAILED DESCRIPTION

In one embodiment, a capsule according to the invention is spherical orsubstantially spherical, preferably perfectly spherical. It is variablein diameter, preferably from 1 to 7 mm in diameter. This diameter willdepend on the use, and may be easily chosen by the person skilled in theart. The weight of a capsule according to the invention is variable; itmay be from 0.5 to 170 mg. In a preferred embodiment, the capsuleaccording to the invention has a diameter of 4.5 to 6.5 mm and a weightof 45 to 140 mg; for example, a diameter of 4.5 to 5.5 mm and a weightof 45 to 80 mg.

A capsule according to the invention is made up of at least one fineenvelope and a liquid core. It may be shiny, transparent ornontransparent in appearance. The core and the envelope may be colored,either the same color or different colors.

The envelope of the capsule according to the invention comprises atleast one film-forming polymer chosen from the film-forming polymersused in the food or pharmaceutical field and known to the person skilledin the art, in particular gelatins, polyvinyl alcohols (PVAs), naturalgums (gum arabic, guar gum, carob gum, gellan gum, pullulan gum, etc.),carreghenans, cellulose derivatives, starch derivatives, etc.

It also comprises at least one plasticizer, which may be of theglycerol, sorbitol, maltitol, triacetine or PEG type, or another polyolwith plasticizing properties, and preferably at least one acid of themonoacid, diacid or triacid type, in particular citric acid, fumaricacid, malic acid, etc. The use of at least one such acid in particularmakes it possible to provide microbiological stability of the envelopeof the capsule and to adjust its physicochemical and sensory propertiesduring dissolving thereof (pH, solubility, etc.).

The thickness of the envelope of the capsule according to the inventionis between approximately 30 and approximately 100 μm, preferably from 50to 65 μm. The envelope represents from 8 to 30% of the weight of thecapsule, preferably 8 to 15%.

The core of the capsule according to the invention is preferentiallycomposed of a mixture of molecules which are hydrophobic or partiallysoluble in ethanol, or of molecules formulated as an oil/water/oilemulsion. It may be composed of one or more lipophilic solventsconventionally used in the food, pharmaceutical or cosmetic industries.They may in particular be triglycerides, and in particular triglyceridesof caprylic and capric acid, mixtures of triglycerides such as vegetableoil, olive oil, sunflower oil, corn oil, groundnut oil, grapeseed oil,wheatgerm oil, mineral oils and silicone oils. The amount of lipophilicsolvent in the core of a capsule according to the invention is of theorder of 0.01 to 90% of the weight of the capsule, preferentially 25 to75%.

The core may also comprise one or more aromatic or fragrancing moleculesas conventionally used in the formulation of flavoring or fragrancingcompositions. Mention will in particular be made of aromatic, terpenicand/or sesquiterpenic hydrocarbons, and more particularly essentialoils, alcohols, aldehydes, phenols, carboxylic acids in their variousforms, aromatic acetals and ethers, nitrogenous heterocycles, ketones,sulfides, disulfides and mercaptans which may be aromatic ornonaromatic. It may also comprise one or more molecules or extracts forcosmetic use.

The core may also comprise one or more “weighting” agents as used inaromatic emulsions. Mention will be made of dammar gum, wood resins ofthe ester gum type, sucrose acetate isobutyrate (SAIB) or brominatedvegetable oils. The function of these weighting agents is to adjust thedensity of the liquid core.

The core may also comprise one or more sweeteners, which may be providedin the form of a solution or suspension in ethanol. Mention will bemade, nonexclusively, of aspartame, NHDC, sucralose, acesulfame,neotame, etc.

The core may also comprise one or more “sensate” aromatic agents, whichprovide either a freshening effect or a hot effect in the mouth. Asfreshening agent, mention will in particular be made of menthylsuccinate and derivatives thereof, in particular Physcool® marketed bythe applicant company. As an agent with a hot effect, mention will bemade of vanillyl ethyl ether.

The exact composition of the core will of course depend on the useenvisaged for the capsule: food, oral hygiene, pharmaceutical, cosmetic,and therefore of the active compound(s) that it is desired to administerto an individual, and may be easily determined by the person skilled inthe art.

The core of a capsule according to the invention represents by weight 70to 92% of the capsule, preferably 80 to 92%, more preferably 85 to 92%.

Several methods of producing capsules are known. Mention will be made ofthe interfacial polymerization or coacervation techniques which make itpossible to obtain capsules which are generally small in size, generallyless than 1 mm, for a perfectly spherical shape, capsules with a largergranulometry exhibiting irregularities in sphericity. Mention may alsobe made of the method of producing soft capsules which makes it possibleto obtain capsules several millimeters in diameter, obtained by weldingtwo hemispherical envelopes.

The capsules according to the invention may be prepared by co-extrusion.The method of co-extrusion consists in co-extruding two liquids, oneexternal and hydrophilic (which will become the envelope), the othercentral and lipophilic (which will become the core), in an oily organicmedium, which leads to the formation of spherical capsules with nowelding joint.

Conventionally, the capsules, after co-extrusion, are kept cold toensure correct gelling of the envelope, and are then centrifuged inorder to remove the surplus oil, then dried and washed with organicsolvent (acetone, ethyl acetate, petroleum ether, etc.) also to removethe surplus oil. In the case of soft capsules, the capsules are treatedby immersion in an organic liquid or an emulsion containing acrosslinking agent of the aldehyde type (formaldehyde, glutaraldehyde,etc.) which makes it possible to obtain a suitable hardness of thecapsules, then dried with a stream of air at 25% humidity (see U.S. Pat.No. 2,578,943). Such a method with drying using dry air or a vacuumleads, however, to insolubilization of the gelatin envelope viacrosslinking reaction.

The capsules according to the invention can be obtained using thefollowing method:

-   -   co-extrusion of the components of the envelope and of the        components of the core,    -   optionally centrifugation,    -   optionally immersion of the capsules obtained in a bath of        ethanol or of anhydrous organic solvent,    -   drying.

More precisely, after formation by co-extrusion, and optionally aftercentrifugation, the capsules are optionally immersed in a bath ofethanol or of any other anhydrous organic solvent, such as ethyl acetateor isopropanol, maintained at a temperature of between 0 and 25° C.,more particularly between 10 and 20° C., making it possible to wash theoil remaining at the surface from the capsules, and then to graduallydehydrate the gelatin film, according to an osmotic equilibrium. Thus,the problems of crosslinking and of insolubilization of the envelope,and therefore the skin effect, are avoided.

When leaving the washing bath, the capsules are dried in a current ofair with controlled temperature and humidity characteristics. Therelative humidity of the drying air is between 20 and 60%,preferentially between 30 and 50%. The temperature of the drying air isbetween 15 and 60° C., preferentially between 35 and 45° C.

In addition, this method makes it possible to obtain capsules which areperfectly spherical and very homogeneous in size.

EXAMPLES Example 1 Capsule for Oral Application of the “Breathfreshener”Type

A capsule 4 mm in diameter and weighing 38 mg, the composition of whichis given in Table 1, is analyzed according to test A. Various capsulesobtained on the market (soft capsule or other), of similar size, and foridentical application, are also tested according to test A, ascomparisons.

The results are given in Table 2. The comparison of the totalsolubilization time and of the breaking up times (in seconds) accordingto test A demonstrate the rapidity of solubilization of the capsuleaccording to the invention.

These results are confirmed by a panel of tasters, who observe theproperties of more rapid solubilization and with no residue, of thecapsule according to the invention.

TABLE 1 Gelatin   7.7% Sorbitol   1.2% Fumaric acid  0.18% Blue FD&C #1(marketed by 0.0001% WARNER JENKINSON) Miglyol 812S  62.92% (marketed byHULS) Flavor  23.6% Physcool ® (freshening agent   4.4% marketed by theapplicant)

TABLE 2 Disintegration or Breaking up solubilization time of the timefor the envelope envelope Capsule according to  12 s  66 s the inventionCapsule 1 - 5 mm  86 s 248 s spherical co-extrusion capsule (CompanyFreund Ltd) Capsule 2 - 3.2 mm  34 s  87 s spherical co-extrusioncapsule (Company Jintan, under the trademark Crystal Dew) Capsule 3 - 9× 6 mm  75 s 302 s soft capsule of the ovoid type (Breathcaps fromBreath Asure Inc.) Capsule 4 - 7.5 × 5.5 mm 105 s 333 s soft capsule ofthe ovoid type (Japan- Citrus)

Example 2 Cinnamon-Flavored Capsule

Two types of capsule according to the invention, 5 mm in diameter, thecompositions 1 and 2 of which are given in Table 3, are analyzedaccording to test A. By way of comparative example, a 5 mm capsule,produced according to Example 2 of U.S. Pat. No. 5,602,707, is alsotested according to test A.

TABLE 3 Capsule according to U.S. Pat. No. Composition Composition5,620,707 1 (%) 2 (%) (%) Gelatin 8.804 7.528 11.484 Sorbitol (70% 0.9780.836 4.362 sol) Fumaric acid 0.196 0.167 Saccharine 0.500 Acesulfame0.644 Aspartyl 0.345 phenyl alanine methyl ester Glycyrrhizin 0.030Propylene 2.435 glycol Polyethylene 25.820 400 Allura Red 0.022 0.0190.003 (red 40) Water 0.500 0.450 1.672 Captex 300 61.280 72.145 10.206(liponate) Cinnamon 22.500 11.029 15.250 flavor Isopropanol 7.280Ethanol 5.000 Sucralose 0.720 0.546 Sucrose 27.249 acetate isobutyrate(SAIB)

The results of the analyses of these capsules, according to test A, andalso in the sensory analysis, are as follows:

TABLE 4 Capsule according to U.S. Pat. No. Composition 1 Composition 25,620,707 Breaking up time 12 +/− 3 s 17 +/− 2 s  48 +/− 3 s Total 65+/− 4 s 70 +/− 2 s 108 +/− 9 s solubilization time Total 40 s 35 s >2min solubilization time after placing in the mouth, by sensoryevaluation

Example 3 Capsule for Controlled Release of Aromatic Molecules

A 5 mm capsule, the composition of which is given in Table 5, isanalyzed according to test A.

TABLE 5 % mg Gelatin 6.63 4.105 Sorbitol 1.78 1.103 Fumaric acid 0.140.088 Miglyol 812S 72.98 45.21 Thymol 2.58 1.60 Menthol 6.28 3.89 Flavormarketed by the 7.35 4.56 applicant Physcool ® 2.26 1.40 TOTAL 100 61.95

The taking of various samples makes it possible to establish the invitro kinetics of release of aromatic molecules in water at 37° C.±1° C.and at pH 6.5. Table 6 indicates the concentration of aromatic moleculesof various samples. A rapidity of release of the order of a few secondsis thus demonstrated.

TABLE 6 Time (seconds) Thymol Menthol MANE flavor 0-5 19 47 32  5-10 2867 46 10-15 22 63 50 15-20 31 90 69 20-30 20 62 57 30-40 7 24 21 40-50 724 23 50-60 4 16 16 60-70 1 6 5 Total 139 ppm 399 ppm 319 ppm

The curves of release of each aromatic molecule (in mg) as a function oftime (in seconds) are given in FIG. 1. It may be noted that most of themolecules are released within 40 s, at most within 70 s.

Example 4 Capsule as Core of a Confectionery Product

A 4 mm capsule weighing 38 mg, the composition of which is given inTable 7, is used as a core provided with a sugar coating so as to obtaina confectionery product for oral hygiene.

TABLE 7 Gelatin    10% Sorbitol   1.2% Fumaric acid   0.2% Blue FD&C #1 0.001% Miglyol 812S 66.099% Flavor and active agents    20% Physcool ®   2% Vitamin E   0.5%

The capsule according to the invention is rapidly solubilized in themouth after dissolving of the coating envelope. The coating envelope isobtained by sugar coating, in a sugar-coating pan, of the capsule usingthe following raw materials: maltitol, gum arabic, shellac gum,vegetable oil, titanium dioxide, menthol MSD powdered flavor marketed bythe applicant. It is observed that the capsule does not leave any skineffect at the end of tasting and leaves a strong flavouring impact inthe mouth.

Example 5 Capsule for Drink Application

A 1 mm capsule weighing 0.53 mg, according to the invention, acomposition of which is given in Table 8, is incorporated into apowdered instant coffee.

TABLE 8 Gelatin   15% Gum arabic 9.89% Sorbitol   3% Fumaric acid 0.01%Caramel dye  0.1% Vegetable oil   36% Volatile coffee flavor marketed  36% by the applicant company

100 ml of hot water at 65° C. are poured. After 10 seconds, the capsulesolubilizes and releases a strong pleasant smell of coffee. The envelopeof the capsule is completely solubilized after 30 seconds.

Example 6 Capsule for Savory Application

A 4 mm capsule weighing 38 mg, according to the invention, thecomposition of which is given in Table 9, is incorporated, at 0.5%, intoa powdered mixture for instant soup.

TABLE 9 Gelatin   7% Gum arabic   4% Sorbitol 1.5% Citric acid 0.5%Sunflower oil  60% Chicken flavor marketed by the  27% applicant company

200 ml of hot water at 65° C. are poured. After 10 seconds, the capsulesolubilizes and releases a strong pleasant smell of chicken. Theenvelope of the capsule is completely solubilized after 30 seconds.

1. A method of preparing a rapidly water-soluble hard capsule having acore comprising one or more core components, and a water-solubleenvelope comprising 6.5 to 15% by weight of a film-forming polymer ofgelatin, 0.8 to 1.5% by weight sorbitol, and either 0.01 to 0.2% byweight fumaric acid or about 0.5% by weight citric acid, wherein thecapsule has a hardness of 1 to 5 Kg/cm² and the envelope of the capsuleexhibits a total solubilization time of less than or equal to 85seconds, using a dissolving device wherein the capsule is crossed by anaqueous flow maintained at 37±0.5° C., pH 6.5, 50 ml/min, said methodcomprising the steps of: providing a liquid mixture of core components,providing a liquid mixture of envelope components comprising a filmforming polymer, a plasticizer, and an acid, co-extruding the liquidmixture of core components and liquid mixture of envelope componentsinto an oily organic solvent to form the capsule having an envelope anda core therein, centrifuging the capsules to remove said oily organicsolvent, immersing the capsule in an anhydrous organic solvent whereinthe temperature of said anhydrous organic solvent is 0° C. to 25° C.,and drying the capsule, provided that the method does not include a stepof immersing the capsule in an organic liquid or an emulsion thatcontains a crosslinking agent.
 2. The method of claim 1 wherein thetemperature of said anhydrous organic solvent is between 10° C. to 20°C.
 3. The method of claim 1, wherein the anhydrous organic solvent isselected from the group consisting of ethanol, ethyl acetate andisopropanol.
 4. The method of claim 3 wherein the anhydrous organicsolvent is ethanol, wherein the temperature of said ethanol is between10° C. to 20° C.
 5. The method of claim 1 wherein the drying stepincludes drying the capsule in a current of air having a relativehumidity between 20 and 60% and a temperature between 15 and 60° C. 6.The method of claim 5 wherein the relative humidity is between 30 and50% and the temperature is between 35 and 45° C.
 7. The method of claim1 wherein the core components are lipophilic and the envelope componentsare hydrophilic.
 8. The method of claim 1 wherein the capsule comprisesan envelope formed from the envelope components and the envelopeexhibits a total solubilization time of less than or equal to 85seconds, using a dissolving device wherein the capsule is crossed by anaqueous flow maintained at 37±0.5° C., pH 6.5, 50 ml/min, said method.9. The method of claim 8 wherein the envelope exhibits a totalsolubilization time of less than or equal to 70 seconds, using adissolving device wherein the capsule is crossed by an aqueous flowmaintained at 37±0.5° C., pH 6.5, 50 ml/min, said method.
 10. A methodof preparing a rapidly water-soluble hard capsule having a corecomprising one or more core components, and a water-soluble envelopecomprising 6.5 to 15% by weight of a film-forming polymer of gelatin,0.8 to 1.5% by weight sorbitol, and either 0.01 to 0.2% by weightfumaric acid or about 0.5% by weight citric acid, wherein the capsulehas a hardness of 1 to 5 Kg/cm² and the envelope of the capsule exhibitsa total solubilization time of less than or equal to 85 seconds, using adissolving device wherein the capsule is crossed by an aqueous flowmaintained at 37±0.5° C., pH 6.5, 50 ml/min, said method comprising thesteps of: providing a liquid mixture of core components, providing aliquid mixture of envelope components comprising a film forming polymerand a plasticizer, co-extruding the liquid mixture of core componentsand liquid mixture of envelope components into a first oily organicsolvent to form the capsule having an envelope and a core therein,centrifuging the capsules to remove said oily organic solvent, immersingthe capsule in a second organic solvent having a temperature selectedfrom the range of 0° C. to 25° C., wherein said second solvent isselected from the group consisting of ethanol, ethyl acetate andisopropanol, and drying the capsule in a current of air having arelative humidity between 20 and 60% and a temperature between 35° C.and 45° C.
 11. The method of claim 10, wherein the temperature of saidsecond organic solvent is between 10° C. to 20° C.
 12. The method ofclaim 10 wherein the second organic solvent is ethanol, wherein thetemperature of said ethanol is between 10° C. to 20° C.
 13. The methodof claim 12 wherein the capsule comprises an envelope formed from theenvelope components and the envelope exhibits a total solubilizationtime of less than or equal to 85 seconds, using a dissolving devicewherein the capsule is crossed by an aqueous flow maintained at 37±0.5°C., pH 6.5, 50 ml/min, said method.